This invention is directed to combinatorial libraries derived from monocyclic amine scaffolds which are derivatized, with building blocks, at various sites of diversity on the scaffold. Further, monocyclic scaffolds are converted into bicyclic scaffolds that are derivatized to afford additional combinatorial libraries of molecules. Also, the present invention is directed to the use of monocyclic and bicyclic amine scaffold in the synthesis of molecules bearing more than one scaffold. These scaffolds are used to prepare diverse combinatorial libraries derived from the many building blocks used at multiple diversity sites.
Traditional processes of drug discovery involve the screening of complex fermentation broths and plant extracts for a desired biological activity or the chemical synthesis of many new compounds for evaluation as potential drugs. The advantage of screening mixtures from biological sources is that a large number of compounds are screened simultaneously, in some cases leading to the discovery of novel and complex natural products with activity that could not have been predicted otherwise. The disadvantages are that many different samples must be screened and numerous purifications must be carried out to identify the active component, often present only in trace amounts. On the her hand, laboratory syntheses give unambiguous products, but the preparation of each new structure requires significant amounts of resources. Generally, the de novo design of active compounds based on the high resolution structures of enzymes has not been successful.
It is thus now widely appreciated that combinatorial libraries are useful per se and that such libraries and compounds comprising them have great commercial importance. Indeed, a branch of chemistry has developed to exploit the many commercial aspects of combinatorial libraries.
In order to maximize the advantages of each classical combinatorial approach, new strategies for combinatorial deconvolution have been developed independently by several groups. Selection techniques have been used with libraries of peptides (Geysen et al., J. Immun. Meth., 1987, 102, 259; Houghten et al., Nature, 1991, 354, 84; Owens et al., Biochem. Biophys. Res. Commun., 1991, 181, 402; Doyle, PCT WO 94/28424; Brennan, PCT WO 94/27719); nucleic acids (Wyatt et al., Proc. Natl. Acad. Sci. U.S.A., 1994, 91, 1356; Ecker et al., Nucleic Acids Res., 1993, 21, 1853); nonpeptides and small molecules (Simon et al., Proc. Natl. Acad. Sci. U.S.A., 1992, 89, 9367; Zuckermann et al., J. Am. Chem. Soc., 1992, 114, 10646; Bartlett et al., WO 91/19735; Ohlmeyer et al., Proc. Natl. Acad. Sci. U.S.A., 1993, 90, 10922; DeWitt et al., Proc. Natl. Acad. Sci. U.S.A., 1993, 90, 6909; Cody et al., U.S. Pat. No. 5,324,483; Houghten et al., PCT WO 94/26775; Ellman, U.S. Pat. No. 5,288,514; Still et al., WO 94/08051; Kauffman et al., PCT WO 94/24314; Carell et al., Angew. Chem. Int. Ed. Engl., 1994, 33, 2059; Carell et al., Angew. Chem. Int. Ed. Engel., 1994, 33, 2061; Lebl et al., WO 94/28028). A review of the above references reveals that the most advanced of these techniques are those for the selection of peptides and nucleic acids. Several groups are working on selection of heterocycles such as benzodiazepines.
The majority of the techniques reported to date involve iterative synthesis and screening of increasingly simplified subsets of oligomers such as peptides and oligonucleotides. Monomers or sub-monomers that have been utilized include amino acids, amino acid-like molecules, i.e. carbamate precursors, and nucleotides, both of which are bifunctional. Utilizing these techniques, libraries have been assayed for activity in either cell-based assays, or for binding and/or inhibition of purified protein targets.
However, the combinatorial chemical approach that has been more commonly utilized of late involves the use of a multifunctional scaffold bearing multiple diversity sites, and derivatizing these sites with varied building blocks to form libraries of diverse small molecule compounds. Libraries may be generated such that each individual compound may be synthesized and isolated separately, or synthesized and used as a mixture of several desirable compounds. A mixture of compounds may be obtained by using a mixture of scaffolds and/or building blocks. However, the synthesis of combinatorial libraries of discrete molecules (parallel synthesis) and of combinatorial pools of molecules (mixture synthesis or split-mix synthesis), and the screening of such libraries, have had significant limitations. These limitations include the need for selective protection and deprotection of desired reactive sites, limited experience with solid-phase chemical reactions, limited access to unique scaffolds for solid-phase synthesis, a small number of reactive functionalities on such scaffolds and often a small number of compound members of classes of building blocks that may be used for library generation. Acids, amines and amino acids are classes of building blocks that have been recognised to be of tremendous utility in combinatorial chemistry because of their reactivity with a variety of functional groups and the availability of large numbers of such compounds of diverse structures from commercial sources. Amino acids, for example, have been extensively used in the synthesis of small molecule combinatorial libraries. The use of amino acids as key building blocks in the construction of substituted heterocycle libraries has been practiced by several groups for exploring known pharmacophores, in cyclic ureas and in xe2x80x98prospecting librariesxe2x80x99 (Bunin and Ellman, J. Am. Chem. Soc., 1992, 114, 10997; DeWitt et al., Proc. Natl. Acad. Sci. USA, 1993, 90, 6909; Nefzi, et al., Tetrahedron Lett., 1997, 38, 931; Bartlett, et al., Book of Abstracts, 213th American Chemical Society National Meeting, San Francisco, 1997, American Chemical Society, Washington D.C., ORGN-273).
The diversity of a combinatorial library is represented by the inherent physical and chemical properties of each scaffold and building block used, the number of different building blocks used during each derivatization step, the physical and chemical properties of the bonds arising from the derivatization chemistry, and the interactions of the scaffold and building block chemistries. Taken together, these interactions provide a unique conformation for each individual compound in the combinatorial library.
In spite of advances in the synthesis of libraries of compounds, there still remains a need in the art for molecules which have fixed preorganized geometry which matches that of target biomolecules, including proteins and enzymes, nucleic acids, and lipids. It is also apparent that when targeting intervention of ligand-receptor interactions of large biomolecular targets that often have large binding sites, active sites, or binding epitopes, the inhibitors, agonists and antagonists desired will also need to be appropriately large. Thus, molecules larger than conventional small molecule drugs, such as oligomeric peptidomimetics, peptoids, and nucleotides, are considered candidates for screening for such activity. Oligomeric molecules derived from other, and often novel preorganized or rigid scaffolds may also be of value when targeting such ligand-receptor interactions. Combinatorially derived libraries should contain compounds which are rigid, yet still possess sufficient flexibility. It is preferable that this be achieved via automated synthesis on solid supports. It is also desirable to have use of scaffolds of some rigidity with multiple sites of diversity that may be selectively reacted via appropriate deprotection schemes during combinatorial library generation. Further, such scaffolds should offer diversity sites that may be reacted with a variety of building blocks, especially those classes of building blocks that comprise a large number of member compounds, such as acids, amines and amino acids.
In accordance with the present invention there are provided monocyclic amine compounds comprising a monocyclic amine scaffold bearing at least two sites of diversity, wherein at least one site of diversity is derived from a primary amino group that is exocyclic or is derived from a secondary amino group that is part of the cyclic structure of the scaffold. Also, the present invention provides libraries of monocyclic amine compounds. As used herein, xe2x80x98libraryxe2x80x99 means a collection of two or more compounds of the invention, as individual compounds or as mixtures. xe2x80x98Libraryxe2x80x99 also means a mixture of diastereomeric compounds.
Compounds of the present invention are of formula I, II, III, IV, V, or VI. It will be recognized by the art-skilled that the monocyclic amine compounds of the present invention bear chiral centers in their scaffolds. Thus, I, II, III, IV, V, and VI, all possess at least one or more chiral centers leading to enantiomeric, and often diastereomeric, molecules. The present invention includes all possible enantiomeric and diastereomeric structures of these monocyclic amine compounds. The monocyclic amine compounds and libraries of compounds of the present invention are of formula I, II, III, IV, V, or VI: 
wherein:
R1 and R1xe2x80x2 are, individually CH2, CH(R2), Cxe2x95x90O, Cxe2x95x90S, S(xe2x95x90O)2, C(xe2x95x90O)NH, C(xe2x95x90S)NH or C(xe2x95x90O)O;
R2 is H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C3-C14 cycloalkyl, substituted or unsubstituted C5-C14 fused cycloalkyl, substituted or unsubstituted C4-C14 heterocyclyl, substituted or unsubstituted C4-C14 heterocyclylalkyl, substituted or unsubstituted C4-C14 heteroaryl; substituted or unsubstituted C4-C14 heteroaralkyl, CH(R7)xe2x80x94NHxe2x80x94R7xe2x80x2 or CH(R7)xe2x80x94NHxe2x80x94R1xe2x80x2xe2x80x94R3; wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy; or R1 and R2, together, are H, or an amino protecting group;
R3 is H;
R4 and R4, are, individually, H, R1-R2 or R11-R12;
R5 is, H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C3-C14 cycloalkyl, substituted or unsubstituted C5-C14 fused cycloalkyl, substituted or unsubstituted C4-C14 heterocyclyl, substituted or unsubstituted C4-C14 heterocyclylalkyl, substituted or unsubstituted C4-C14 heteroaryl; substituted or unsubstituted C4-C14 heteroaralkyl, xe2x80x94R1-R2, or N(R8)(R9)xe2x80x94C(xe2x95x90O); wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy;
R6 is, H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C3-C14 cycloalkyl, substituted or unsubstituted C5-C14 fused cycloalkyl, substituted or unsubstituted C4-C14 heterocyclyl, substituted or unsubstituted C4-C14 heterocyclylalkyl, substituted or unsubstituted C4-C14 heteroaryl; substituted or unsubstituted C4-C14 heteroaralkyl, xe2x80x94R1-R2, or xe2x80x94C(xe2x95x90O)Oxe2x80x94R3; wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy; or R5 and R6, together, are (CH2)nd, (CH2)ndxe2x80x94Oxe2x80x94(CH2)ne, (CH2)ndxe2x80x94N(R10)xe2x80x94(CH2)ne, or (CH2)ndxe2x80x94Sxe2x80x94(CH2)ne, wherein R10 is substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C14 aryl, or substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C4-C14 heteroaryl; substituted or unsubstituted C4-C14 heteroaralkyl;
R7 is H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C3-C14 cycloalkyl, substituted or unsubstituted C5-C14 fused cycloalkyl, substituted or unsubstituted C4-C14 heterocyclyl, substituted or unsubstituted C4-C14 heterocyclylalkyl, substituted or unsubstituted C6-C14 heteroaryl; substituted or unsubstituted C6-C14 heteroaralkyl, or groups such as those attached to the a-position of amino acids, wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy;
R7 is H or an amino protecting group;
R8 and R9 are each, independently, H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C3-C14 cycloalkyl, substituted or unsubstituted C5-C14 fused cycloalkyl, substituted or unsubstituted C4-C14 heterocyclyl, substituted or unsubstituted C4-C14 heterocyclylalkyl, substituted or unsubstituted C4-C14 heteroaryl; substituted or unsubstituted C4-C14 heteroaralkyl, wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy; or R8 and R9, together, are (CH2)nd, (CH2)ndxe2x80x94Oxe2x80x94(CH2)ne, (CH2)ndxe2x80x94N(R10)xe2x80x94(CH2)ne, or (CH2)ndxe2x80x94Sxe2x80x94(CH2)ne, wherein R10 is substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C14 aryl, or substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C4-C14 heteroaryl; substituted or unsubstituted C4-C14 heteroaralkyl;
R11 is a linker moiety;
R12 is a solid support;
W, X, Y, and Z are, independently, CHxe2x80x94R3, O, S, CHN(R4)(R4xe2x80x2), Nxe2x80x94R1-R2 or CHxe2x80x94CH(R3)N(R5)(R6);
ma, mb, mc and md are, independently, 0, 1, 2, or 3;
na, nb and nc are each, independently, 0 to 2, wherein the sum of na, nb and nc is from 0 to 5; and
nd and ne are each, independently, 1 to 4; provided that said compound is not:
N-[1-[1,1xe2x80x2-biphenyl]-4-ylsulfonyl)-5-[[[4-[(2,4-dioxo-5-thiazolidinylidene)methyl]bezoy]amino]methyl]-3-pyrrolidinyl]-4-[(3-oxo-2(3H)-isothizolyl)methyl]xe2x80x94, [3S-[3.alpha., 5.alpha.(E)]]-benzamide; or
N-[(4-amino-2-pyrrolidinyl)methyl]-3-methyl-L-valyl-L-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-, (2S-trans)-, tris (trifluoroacetate)-L-glutamine; or
N-[[1-[(1,1-dimethylethoxy)carbonyl]-4-[[(1,1-dimethyletyhoxy)carbonyl]amino]-2-pyrrolidinyl]methyl]-3-methyl-L-1,2,3,4-tetrahydor-3-isoquinolinecarbonyl-, (2S-trans)-, tris (trifluoroacetate)- L-glutamine; or.
N-[(4-amino-2-pyrrolidinyl)methyl]-3-methyl-L-valyl-L-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-, (2S-trans)-trifluoroacetate L-glutamine; or
N-[(4-amino-2-pyrrolidinyl)methyl]-3-methyl-L-valyl-L-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-, (2S-trans)-L-glutamine; or
3-[[[1-[(4-chlorophenyl)sulfonyl]-4-[[(4-chlorophenyl)sulfonyl]amino]-2-pyrrolidinyl]methyl]amino]-(2S-trans)-benzoic acid; or
4-azido-2-(azidomethyl)-1-(p-tolylsulfonyl)-, (xe2x88x92)-pyrrolidine.
This invention also provides methods for preparing the monocyclic amine compounds of formula I, II, III, IV, V and VI. Further, in accordance with this invention, there are provided methods for preparing libraries of monocyclic amine compounds, comprising:
(a) selecting a monocyclic amine scaffold of formula VII, VIII, IX, X, XI or XII: 
wherein:
Z1 is an amino protecting group;
Z2 is a hydroxyl protecting group;
Z3 is H;
Z4 is N3, N-Pg or NH-Pg, wherein Pg is an amino protecting group;
R3 is H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C3-C14 cycloalkyl, substituted or unsubstituted C5-C14 fused cycloalkyl, substituted or unsubstituted C4-C14 heterocyclyl, substituted or unsubstituted C4-C14 heterocyclylalkyl, substituted or unsubstituted C4-C14 heteroaryl; substituted or unsubstituted C4-C14 heteroaralkyl, wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy;
W, X, Y, and Z are, independently, CHxe2x80x94R3, O, S, CHxe2x80x94NHxe2x80x94Z3, Nxe2x80x94Z1, CHxe2x80x94Oxe2x80x94Z2 or CHxe2x80x94CH(R3)Z4; and
ma, mb, mc and md are, independently, 0, 1, 2, or 3;
(b) attaching said monocyclic amine scaffold to a solid support via a hydroxy or amino group to form a solid support-bound scaffold (i.e. Z3 is a solid support or a linker moiety attached to a solid support);
(c) treating said amino protecting group with a deprotection reagent to form a free amino group (i.e. Z1 is H);
(d) derivatizing the free amino group with a suitable building block;
(e) treating said hydroxyl protecting group, if present, with a deprotecting reagent to form a free hydroxyl group (i.e. Z2 is H), or reduction of the azido group to form a free amino group;
(f) reacting the free hydroxyl or amino group with a building block or activating reagent;
(g) derivatizing the activated hydroxyl or amino group with another suitable building block; and
(h) cleaving the substituted monocyclic amine compound from the solid support.
It will be recognized by the art-skilled that all the classes of the monocyclic amine scaffolds of the present invention bear chiral centers. Thus scaffolds, VII, VIII, IX, X, XI and XII, all possess at least one or more chiral centers in their structure leading to enantiomeric, and often diastereomeric, compounds. The present invention includes all possible enantiomeric and diastereomeric structures of these monocyclic amine scaffolds.
The present invention also provides compounds comprising a bicyclic scaffold bearing at least two sites of diversity, wherein the bicyclic scaffold is readily generated from the aforementioned monocyclic amine scaffold via intramolecular cyclization. Of the many sites of diversity on the bicyclic amine scaffolds of the present invention, at least one site of diversity is derived from a primary amino group that is exocyclic or from a secondary amino group that is part of the cyclic structure of the scaffold. Also, the present invention provides libraries of bicyclic amine compounds derived from bicyclic scaffolds. Compounds of the libraries of the present invention are of formula XIII, XIV, or XV. It will be recognized by the art-skilled that the bicyclic amine compounds of the present invention bear chiral centers. Thus, compounds of formula XIII, XIV and XV, all possess at least one or more chiral centers in their scaffold structure leading to enantiomeric, and often diastereomeric, compounds. The present invention includes all possible enantiomeric and diastereomeric structures of these bicyclic amine compounds, except where the structure explicitly shows a specific stereochemistry. The bicyclic amine compounds and libraries of compounds of the present invention are of formula XIII, XIV, or XV: 
wherein:
R1 and R1xe2x80x2 are, individually CH2, CH(R2), Cxe2x95x90O, Cxe2x95x90S, S(xe2x95x90O)2, C(xe2x95x90O)NH, C(xe2x95x90S)NH or C(xe2x95x90O)O;
R2 is H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C3-C14 cycloalkyl, substituted or unsubstituted C5-C14 fused cycloalkyl, substituted or unsubstituted C4-C14 heterocyclyl, substituted or unsubstituted C4-C14 heterocyclylalkyl, substituted or unsubstituted C4-C14 heteroaryl; substituted or unsubstituted C4-C14 heteroaralkyl, CH(R7)xe2x80x94NHxe2x80x94R7xe2x80x2 or CH(R7)xe2x80x94NHxe2x80x94R1xe2x80x2xe2x80x94R3; wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy; or R1 and R2, together, are H, or an amino protecting group;
R3 is H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C3-C14 cycloalkyl, substituted or unsubstituted C5-C14 fused cycloalkyl, substituted or unsubstituted C4-C14 heterocyclyl, substituted or unsubstituted C4-C14 heterocyclylalkyl, substituted or unsubstituted C4-C14 heteroaryl; substituted or unsubstituted C4-C14 heteroaralkyl, wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy;
R4 and R4xe2x80x2 are, individually, is H, N(R8)(R9)C(xe2x95x90O), R1-R2 or R11-R12;
R7 is H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C3-C14 cycloalkyl, substituted or unsubstituted C5-C14 fused cycloalkyl, substituted or unsubstituted C4-C14 heterocyclyl, substituted or unsubstituted C4-C14 heterocyclylalkyl, substituted or unsubstituted C6-C14 heteroaryl; substituted or unsubstituted C6-C14 heteroaralkyl, or groups such as those attached to the a-position of naturally-occurring or non-naturally occurring amino acids of D- or L-configuration, wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy;
R7xe2x80x2 is H or an amino protecting group;
R8 and R9 are each, independently, H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C3-C14 cycloalkyl, substituted or unsubstituted C5-C14 fused cycloalkyl, substituted or unsubstituted C4-C14 heterocyclyl, substituted or unsubstituted C4-C14 heterocyclylalkyl, substituted or unsubstituted C4-C14 heteroaryl; substituted or unsubstituted C4-C14 heteroaralkyl, wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy; or R8 and R9, together, are (CH2)nd, (CH2)ndxe2x80x94Oxe2x80x94(CH2)ne, (CH2)ndxe2x80x94N(R10)xe2x80x94(CH2)ne, or (CH2)ndxe2x80x94Sxe2x80x94(CH2)ne, wherein R10 is substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C14 aryl, or substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C4-C14 heteroaryl; substituted or unsubstituted C4-C14 heteroaralkyl;
R11 is a linker moiety; and
R12 is a solid support;
W, X, Y, and Z are, independently, CHxe2x80x94R3, O, S, CHN(R4)(R4xe2x80x2), Nxe2x80x94R1-R2, CHxe2x80x94Oxe2x80x94R4 or CHxe2x80x94CH(R3)N(R5)(R6); and
ma, mb, mc and md are, independently, 0, 1, 2, or 3.
This invention also provides methods for preparing the bicyclic amine compounds of formula XIII, XIV, and XV. Further, in accordance with this invention, there are provided methods for preparing libraries of bicyclic amine compounds comprising:
(a) selecting a monocyclic amine scaffold of formula X, XI, or XII: 
wherein:
Z1 is an amino protecting group;
Z2 is a hydroxyl protecting group;
Z3 is H;
Z4 is N3, N-Pg or NH-Pg, wherein Pg is an amino protecting group;
R3 is H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C3-C14 cycloalkyl, substituted or unsubstituted C5-C14 fused cycloalkyl, substituted or unsubstituted C4-C14 heterocyclyl, substituted or unsubstituted C4-C14 heterocyclylalkyl, substituted or unsubstituted C4-C14 heteroaryl; substituted or unsubstituted C4-C14 heteroaralkyl, wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy;
W, X, Y, and Z are, independently, CHxe2x80x94R3, O, S, CHxe2x80x94NHxe2x80x94Z3, Nxe2x80x94Z1, CHxe2x80x94Oxe2x80x94Z2 or CHxe2x80x94CH(R3)Z4; and
ma, mb, mc and md are, independently, 0, 1, 2, or 3;
(b) attaching said monocyclic amine scaffold to a solid support via a hydroxy or amino group to form a solid support bound scaffold (i.e. Z3 is a solid support or a linker moiety attached to a solid support);
(c) reacting the amino group, if present, that attaches the scaffold to the solid support with a suitable building block;
(d) treating said amino protecting group of said scaffold with a deprotection reagent to form a free amino group (i.e. Z1 is H);
(e) derivatizing the free amino group with an a-amino acid building block having an N-terminus protecting group;
(f) deprotecting the N-terminus protecting group with a deprotection reaction to form an unmasked amine;
(g) reacting the unmasked amine with an appropriate activating reagent to form an activated amino group;
(h) treating said hydroxyl protecting group of said scaffold with a deprotection reagent to form a free hydroxy group (i.e. Z2 is H);
(i) subjecting the support bound intermediate of step
(h) to cyclization conditions such that the free hydroxy group reacts with the activated amino group from step (g) to generate a bicyclic amine scaffold of formula XVI, XVII or XVIII: 
wherein:
Z1 is an amino protecting group;
Z3 is H;
Z4 is N3, N-Pg or NH-Pg, wherein Pg is an amino protecting group;
R3 is H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C3-C14 cycloalkyl, substituted or unsubstituted C5-C14 fused cycloalkyl, substituted or unsubstituted C4-C14 heterocyclyl, substituted or unsubstituted C4-C14 heterocyclylalkyl, substituted or unsubstituted C4-C14 heteroaryl; substituted or unsubstituted C4-C14 heteroaralkyl, wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy;
R7 is H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C3-C14 cycloalkyl, substituted or unsubstituted C5-C14 fused cycloalkyl, substituted or unsubstituted C4-C14 heterocyclyl, substituted or unsubstituted C4-C14 heterocyclylalkyl, substituted or unsubstituted C6-C14 heteroaryl; substituted or unsubstituted C6-C14 heteroaralkyl, or groups such as those attached to the a-position of naturally-occurring or non-naturally occurring amino acids of D- or L-configuration, wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy;
W, X, Y, and Z are, independently, CHxe2x80x94R3, O, S, CHxe2x80x94NHxe2x80x94Z3, Nxe2x80x94Z1, CHxe2x80x94Oxe2x80x94Z2 or CHxe2x80x94CH(R3)Z4; and
ma, mb, mc and md are, independently, 0, 1, 2, or 3;
(j) removing the activating group attached to the amino group of the bicyclic amine scaffold to form a free amino group;
(k) reacting the free amino group with a suitable building block; and
(l) cleaving the substituted bicyclic amine compound from the solid support.
It will be recognized by the art-skilled that the bicyclic amine scaffolds and bicyclic amine compounds of the present invention bear chiral centers. Thus compounds of formula XIII, XIV and XV, possess at least one or more chiral centers in their structure leading to enantiomeric and often diastereomeric compounds. The present invention includes all possible enantiomeric and diastereomeric structures of the bicyclic amine molecules.
In an additional aspect, the present invention also provides oligomeric amine compounds comprising at least two or more monocyclic amine or bicyclic amine scaffolds, wherein the scaffolds are connected to each other via a variety of covalent inter-scaffold linkages including, but not limited to carbamate, alkylamine, urea, thiourea and amindine. These oligomeric amine compounds bear multiple sites of diversity that arise not only from the diversity sites offered by their component scaffolds, but also at sites that are created from the nature of the covalent inter-scaffold linkage. Also, the present invention provides libraries of such oligomeric compounds derived from multiple scaffolds. It will be recognized by the art-skilled that the oligomeric amine compounds of the present invention bear chiral centers. Thus oligomeric amine compounds of the present invention possess multiple chiral centers in their component scaffolds leading to enantiomeric, and often diastereomeric, compounds. The present invention includes all possible enantiomers and diastereomers of these compounds.
This invention also provides methods for preparing the oligomeric amine compounds. Further, in accordance with this invention, there are provided methods for preparing libraries of oligomeric amine compounds, comprising:
(a) selecting a monocyclic amine scaffold of formula VII, VIII, IX, X, XI, or XII: 
wherein:
Z1 is an amino protecting group;
Z2 is a hydroxyl protecting group;
Z3 is H;
Z4 is N3, N-Pg or NH-Pg, wherein Pg is an amino protecting group;
R3 is H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aralkyl, substituted or unsubstituted C3-C14 cycloalkyl, substituted or unsubstituted C5-C14 fused cycloalkyl, substituted or unsubstituted C4-C14 heterocyclyl, substituted or nsubstituted C4-C14 heterocyclylalkyl, substituted or nsubstituted C4-C14 heteroaryl; substituted or unsubstituted C4-C14 heteroaralkyl, wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy;
W, X, Y, and Z are, independently, CHxe2x80x94R3, O, S, CHxe2x80x94NHxe2x80x94Z3, Nxe2x80x94Z1, CHxe2x80x94Oxe2x80x94Z2 or CHxe2x80x94CH(R3)Z4; and
ma, mb, mc and md are, independently, 0, 1, 2, or 3;
(b) attaching said monocyclic amine scaffold to a solid support to form a solid support-bound scaffold;
(c) derivatizing said scaffold with a suitable building block to form a substituted scaffold, or effecting a cyclization reaction to form a bicyclic scaffold;
(d) removing the amino protecting group or hydroxy protecting group of said scaffold from step (c) with a deprotection reagent to form a free amino or hydroxy group;
(e) activating the amino or hydroxy group with an appropriate activating reagent;
(f) reacting the intermediate from step (e) with another monocyclic amine scaffold;
(g) repeating steps (c), (d), (e) and (f) in sequence, as many times as desired to form an oligomeric amine compound; and
(h) cleaving said oligomeric amine compound from the solid support.
It will be recognized by the art-skilled that these oligomeric amine compounds of the present invention bear at least one or more chiral centers in their structure leading to enantiomeric, and often diastereomeric, compounds. The present invention includes all possible enantiomers and diastereomers of these oligomeric amine compounds.